Substituted mercapto-acetamides



United States Patent ""ce 3,182,081 SUBSTlTUTED MERCAPTlB-ACETAMIDESMoses Wolf Goldberg, Upper Montclair, and Harms Hanina Lehr, Montclair,N.J., assignors to Hotlmann- La Roche Inc, Nutley, N.Y., a corporationof New .l ersey No Drawing. Filed Apr. 2, 1963, Ser. No. 269,871

6 Claims. (Cl. 260-535) This invention relates to substituteda-mercapto-acetamides and to processes for their preparation. Moreparticularly, this invention relates to a-mercapto-acetamides of theformula z '5 S( 2)r- (I) wherein R is hydrogen, lower alkyl or loweralkoxy lower alkyl, e.g., methyl, ethyl, isopropyl, butyl, ethoxyethyl,etc., and n is a whole number from 2 to 6. The term lower alkyl as usedherein is to be understood to include straight or branched chain alkylgroups having from 1 to 7 carbon atoms.

The above compounds of Formula 1 exhibit hypnotic and muscle relaxantactivity and are useful as hypnotics and muscle relaxants.

Examples of compounds of Formula I include: oc- (Z-ethoxyethylmercapto-oz,a-diethylacetamide,

OL- (Z-methoxyethylmercapto) -a,u-diethylacetamide,

a- 2-butoxyethylmercapto -a,oc-diethylacetamide,

a-(3-hydroxypropylmercapto)-a,u-diethy1acetamide,

oz- (3-methoxypropylmercapto -O6,0C-dlthylaCtaII1ld6,

oc- 3-ethoxypropylmercapto -a,ot-diethylacetamide,

0..- (5 -ethoxypentylmercapto -a,a-diethylacetamide,

ix- 6-ethoxyhexylmercapto -a,a-diethylacetamide,

a- [2- (Z-ethoxyethoxy -ethy1mercapto] -ot,a-diethylacetamide,etc.

The compounds of Formula I can be prepared by the steps of (a)condensing a dialkali metal salt, e.g., a disodium salt, ofwmercapto-a,a-diethylacetic acid with a halo ether or alcohol having theformula R0 (CH ),,X (II) wherein R and n have the meanings given abovefor Formula I and X is halogen, e.g., chlorine, bromine, or iodine, toform a reaction product of the formula 0,415 s-(oH,)..-oR (III) whereinR and n have the meanings given above for Formula I, and (b) convertingthe compound of Formula 111 into a compound of Formula I by knownmethods, e.g., by treatment with an inorganic acid halide, e.g., PCl PBrPCl SOCI etc., followed by reaction of the resulting product withammonia. Where R is hydrogen in Formula III, the Ol-I group must beprotected, such as by a lower alkan'oyl group, until after formation ofthe amide, whereupon the protecting group is removed, e.g., byhydrolysis.

The invention will be better understood from a consideration of thefollowing examples which are given for illustration purposes only andare not meant to limit the invention.

EXAMPLE 1 a- (.Z-methoxyethylm ercapto) -a,ot-diethy lacetamid e 30 g.of e-mercapto-oc,ot-diethylacetic acid, dissolved in 50 cc. of ethanol,is added slowly in a nitrogen atmos- 3,13Z,8l Patented May 4, 1965 phereto a cooled and stirred solution of 9,2 g. of sodium in 400 cc. ofethanol. 31 g. of Z-methoxyethylbromide in 50 cc. of ethanol is thenadded gradually. The mixtrue is stirred at room temperature for 16hours. A white solid precipitates during the reaction. Withoutfiltration, the ethanol is removed in vacuo, and the residue dissolvedin water. The solution is acidified, extracted with ether, and theextract dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo, yielding 26 g. ofa-(Z-methoXyethylmercapto)-u, x-diethylacetic acid as a colorless oil,boiling at 131l33/O.15 mm.

26 g. of ot-(Z-methoxyethylmercapto)-a,ot-diethylacetic acid is refluxedfor 2 hours with 65 cc. of thionyl chloride. After removal of the excessthionyl chloride, the residue is fractionated in vacuo, yielding 25 g.of u-(2- methoxyethylmercapto)-e,a-diethylacetylchloride, boiling at100-102/0.4 mm.

25 g. of a-(Z-methoxyethylmercapto)a t-diethylacetylchloride in 100 cc.of other is added gradually to a solution of 15 g. of ammonia in 300 cc.of ether. After standing for 5 hours at room temperature, water is addedto dissolve the precipitated ammonium chloride. The organic layer isseparated and dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo. zx-(Z-methoxyethylmercapto)we,diethylacetamide is obtained as a colorless oil boiling at l42l44/ 0.3mm., which solidifies in the refrigerator to white crystals melting at35-37. Yield 15 g.

EXAMPLE 2 oa-(Z-ethoxyethylmercapto)-a,a-diethylacetamide 30 g. ofrx-mercapto-a,ot-diethylacetic acid, dissolved in 50 cc. of ethanol, isadded slowly in a nitrogen atmosphere to a cooled and stirred solutionof 9.2 g. of sodium in 400 cc. of ethanol. 37 g. of 2-ethoxyethylbromidein 50 cc. of ethanol is then added gradually and the mixture stirred atroom temperature for 16 hours. A white solid precipitates during thereaction. Without filtration, the ethanol is removed in vacuo, and theresidue dissolved in water. The solution is acidified, extracted withether, and the extract dried over sodium sulfate. After removal of theether, the residue is fractionated in vacuo, yielding 34 g. ofa-(Z-ethoxyethylmercaptoyoga-diethylacetic acid as a colorless liquidboiling at 148-152/0.5

34 g. of a-(2-ethoxyethylmercapto)-a,a-diethylacetic acid is refluxedfor 2 hours with cc. of thionyl chloride. After removal of the excessthionyl chloride, the residue is fractionated in vacuo, yielding 33 g.of Ot-(Z- ethoxyethylmercaptoymu diethylacetylchloride, boiling at93/0.2 mm.

33 g. of a-(2-ethoxyethylmercapto)-a,a-diethy1acetylchloride in cc. ofether is added gradually to a solution of 18 g. of ammonia in 500 cc. ofether. After standing at room temperature for 5 hours, water is added todissolve the precipitated ammonium chloride. The organic layer isseparated and dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo. a-(2-ethoxyethylmercapto-u,ot-diethylacetamide is obtained as a colorless liquid boiling at134-l37/O.4 mm., and solidifying in the refrigerator to white crystalsmelting at 3435. Yield 23 g.

EXAMPLE 3 ot-(Z-butoxyethylmercapto)-ot,a-dielhylacetamide 30 g. ofa-mercapto-a,oc-diethylacetic acid, dissolved in 50 cc. of ethanol, isadded slowly in a nitrogen atmosphere to a cold and stirred solution of9.2 g. of sodium in 400 cc. of ethanol. 44 g. of 2-butoxyethylbrornidein Us 100 cc. of ethanol is then added gradually and the mixture stirredat room temperature for 16 hours. A white solid precipitates during thereaction. Without filtration, the ethanol is removed in vacuo, and theresidue dissolved in water. The solution is acidified, extracted withether, and the extract dried over sodium sulfate. After removal of theether, the residue is fractionated in vacuo, yielding 34 g. oft-(Z-blllOXYlhYllllICflPtO)-0c,et diethylacetic acid as a colorlessliquid boiling at 149- 154/ 0.5 mm.

34 g. of a-(2-butoxyethylmercapto)- x,a-diethylacetic acid is refluxedfor 2 hours with 80 cc. of thionyl chloride. After removal of the excessthionyl chloride, the residue is fractionated in vacuo, yielding 34 g.of (It-(2- butoxyethylmercapto)-a,a-diethylacetylchloride boiling atll1l16/0.3 mm.

34 g. of a-(2-butoxyethylmercapto)-a,a-diethylacetylchloride in 100 cc.of ether is added gradually to a solution of 20 g. of ammonia in 500 cc.of ether. After standing for 6 hours at room temperature, water is addedto dissolve the precipitated ammonium chloride. The organic layer isseparated and dried over sodium sulfate. After removal of the ether, theresidue is frac tionated in vacuo.a-(Z-butoxyethylmercapto)-a,ot-diethylacetamide is obtained as acolorless liquid boiling at 140-144/0.2 mm. Yield 23 g.

EXAMPLE 4 Ot- (3 -lzydroxypr0py lm ercapto -u,ot-di ethylacetam id e 60g. of a-mercaptodiethylacetic acid in 100 cc. of ethanol is added slowlyin a nitrogen atmosphere to a cooled and stirred solution of 18.4 g. ofsodium in 800 cc. of ethanol. 60 g. of 3-bromo-1-propanol in 100 cc. ofethanol is then added gradually, and the mixture stirred at roomtemperature for 16 hours. A white solid precipitates during thereaction. Without filtration, the ethanol is removed in vacuo, and theresidue dissolved in water. The solution is acidified, extracted withether, and the extract dried over sodium sulfate. After removal of theether, the residue is fractionated in vacuo, yielding 66 g. ofot-(3-hydroxypropylmercapto)-a,a-diethylacetic acid as colorless oilboiling at l75l80/O.3 mm.

25 g. of u-(3-hydroxypropylmercapto)-a,z-diethylacetic acid, dissolvedin 30 cc. of benzene, is added in portions to 31 g. of acetylchloride in300 cc. of benzene, and the mixture refluxed for 3 hours. After removalof the solvent, the liquid residue is mixed with 50 cc. of thionylchloride and refluxed for 3 hours. The residue obtained after removal ofthe excess thionyl chloride is dissolved in 100 cc. of ether and thesolution added gradually to a solution of 15 g. of ammonia in 400 cc. ofether. After standing for 6 hours at room temperature, Water is added todissolve the precipitated ammonium chloride. The organic layer isseparated and dried over sodium sulfate. After removal of the ether, aliquid residue is obtained, which solidifies slowly. Recrystallizationfrom benzene-petroleum ether yields 24 g. ofa-(3-acetoxypropylmercapto)-a,ot-diethylacetamide as White crystalsmelting at 6567.

23 g. of u-(3-acetoxypropylmercapto)-a,a-diethylacetamide is dissolvedin 400 cc. of 2.5 percent aqueous sodium hydroxide and kept overnight atroom temperature. The mixture is then acidified and extracted withether. The ether extract is dried over sodium sulfate. After removal ofthe ether, the residue is fractionated in vacuo.ot-(3-hydroxypropylmercapto)-a,a-diethylacetamide is obtained as acolorless liquid boiling at 168-l69/0.3 mm. Yield 14 g.

EXAMPLE a-(3-methoxypropylmercapto)-ot,a-diethylacetamide 27 g. ofa-mercapto-a,u-diethylacetic acid, dissolved in 50 cc. of ethanol, isadded slowly, in a nitrogen atmosphere, to a cooled and stirred solutionof 8.3 g. of sodium in 350 cc. of ethanol. 22 g. of3-methoxypropylchloride in 50 cc. of ethanol is then added gradually,and the mixture is stirred at room temperature for 16 hours. A whitesolid precipitates during the reaction. Without filtration, the ethanolis removed in vacuo, and the residue dissolved in water. The solution isacidified, extracted With ether, and the extract dried over sodiumsulfate. After removal of the ether, the residue is fractionated invacuo, yielding 25 g. of a-(3-methoxypropylmercapto)- a,a-diethylaceticacid as a colorless oil, boiling at ll58/0.4 mm.

g. of a-(3-methoxypropylmercapto)-a,a-diethylacetic acid is refluxedwith 25 cc. of thionyl chloride for 2 hours. After removal of the excessthionyl chloride,

' the residue is fractionated in vacuo, yielding 23 g. of ar 1300 cc. ofethanol.

(3 methoxypropylmercapto) a, diethylacetylchloride boiling at 9910l/0.3mm.

23 g. of a-(3-methoxypropylmercapto)-a,a-diethylacetylchloride in 100cc. of ether is added gradually to a solution of 10 g. of ammonia in 300cc. of ether. After standing at room temperature for 5 hours, water isadded to dissolve the precipitated ammonium chloride. The organic layeris separated and dried over sodium sulfate. After removal of the ether,the residue is fractionated in vacuo. a (3 methoxypropylmercapto) ,0;diethylacetamide is obtained as a colorless liquid boiling at 148/0.3mm. Yield 16 g.

EXAMPLE 6 0L- (3-etlzoxypropylmercapto -a,a-dietl1ylacetam Me 123 g. ofa-mercapto-a,a-diethylacetic acid in 100 cc. of ethanol is addedgradually in a nitrogen atmosphere to a cooled and stirred solution of37.7 g. of sodium in 144 g. of 3-ethoxypropylbromide in 100 cc. ofethanol is then added and the mixture stirred for 16 hours at roomtemperature. A white solid precipitates during the reaction. Withoutfiltration, the ethanol is removed in vacuo, and the residue dissolvedin water. The solution is acidified, extracted with ether, and .theextract dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo, yielding 143 g. ofu-(3-ethoxypropylmercapto)-ot,tx-diethylacetic acid as a colorless oil,boiling at 154-l59/ 0.5 mm.

143 g. of a-(3-ethoxypropylmercapto)-a,a-diethylacetic acid are mixedwith 200 cc. of thionyl chloride and refluxed for 2 /2 hours. Afterremoval of the excess thionyl chloride, the residue is fractionated invacuo,

yielding 150 g. of ot-(3-ethoxypropylmercapto)wot-diethylacetylchlorideboiling at 102-106/ 0.3 mm.

g. of u-(3-ethoxypropylmercapto)-u,a-diethylacetylchloride dissolved in200 cc. of ether is gradually added to a solution of 40 g. of ammonia in800 cc. of

ether. After standing at room temperature for 6 hours,

water is added to dissolve the precipitated ammonium chloride. Theorganic layer isseparated and dried over sodium sulfate. After removalof the ether, e-(3-ethoxypropylmercapto)-a,a-diethylacetamide isobtained as a liquid which solidifies slowly in the cold. After tworecrystallizations from pentane, white crystals are obtained, melting at41-42. Yield 1.30 g.

EXAMPLE 7 tx-(3-metlz0xybutylmercapto)-a,a-diethylacetar12ide 30 g. ofe-mercapto-a,a-diethylacetic acid dissolved in 50 cc. of ethanol isadded slowly in a nitrogen atmosphere to a cooled and stirred solutionof 9.2 g. of sodium in 400 cc. of ethanol. 35 g. of3-methoxybutylbromide in 50 cc. of ethanol is then added gradually, andthe mixture stirred at room temperature for 16 hours. A white solidprecipitates during the reaction. Without filtration, the etha- 1101 isremoved in vacuo, and the residue dissolved in water. The solution isacidified, extracted with ether, and the extract dried over sodiumsulfate. After removal of the ether, the residue is fractionated invacuo yielding 38 g. of a-(3-methoxybutylmercapto)-a,a-dietl1ylaceticacid as a colorless oil boiling at 144-149/ 0.3 mm.

38 g. of a-(3-methoxypropylmercapto)-a,a-diethylace tic acid is refluxedwith 50 cc. of thionyl chloride for 2 hours. After removal of the excessthionyl chloride, the residue is fractionated in vacuo, yielding 35 g.of a-(3- methoxybutylmercapto) a,a-diethylacetylchloride boiling at100-103/0.3 mm.

35 g. of a-(3-methoxybutylmercapo)- x,a-diethylacetylchloride in 100 cc.of ether is added gradually to a solution of 15 g. of ammonia in 500 cc.of ether. After standing for 5 hours at room temperature, water is addedto dissolve the precipitated ammonium chloride. The organic layer isseparated and dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo. a-(3-metl1oxybutylmercapto)-a,a-diethylacetamide is obtained as acolorless oil, boiling at 145l46/0.4 mm. Yield 22 g.

EXAMPLE 8 a- (5 -ethxypentylmercapr0)-a,a-diethylacetamide 30 g. ofu-mercapto-u,a-diethylacetic acid dissolved in 50 cc. of ethanol isadded slowly in a nitrogen atmosphere to a cooled and stirred solutionof 9.2 g. of sodium in 400 cc. of ethanol. 40 g. ofS-ethoxypentylbromide in 50 cc. of ethanol is then added gradually, andthe mixture stirred for 16 hours at room temperature. A white solidprecipitates during the reaction. Without filtration, the ethanol isremoved in vacuo, and the residue dissolved in water. The solution isacidified, extracted with ether, and the extract dried over sodiumsulfate. After removal of the ether, the residue is fractionated invacuo, yielding 35 g. of a-(S-ethoxypentylmercapto)-a,a-diethylaceticacid, boiling at 185187/1 mm.

35 g. of a-(S-ethoxypentylmercapto)-a,a-diethylacetic acid is refluxedwith 70 cc. of thionyl chloride for 2 hours. After removal of the excessthionyl chloride, the residue is fractionated in vacuo, yielding 33 g.of a-(S-ethoxypentylmercapto)-a,a-diethylacetylchloride boiling at135138/ 0.5 mm.

33 g. of a-(S-ethoxypentylmercapto)-a,a-diethylacetyh chloride in 100cc. of ether is added slowly to a solution of 15 g. of ammonia in 500cc. of ether. After standing for 4 hours at room temperature, water isadded to dissolve the precipitated ammonium chloride. The organic layeris separated and dried over sodium sulfate. After removal of the ether,the residue is fractionated in vacuo.a-(S-ethoxypropylmercapto)-a,a-diethylacetarnide is obtained as acolorless liquid, boiling at 163-166/0.4 Yield 22 g.

EXAMPLE 9 a-(6-eth0xyhexylmercapto)-u,a-diethylacetamide 30 g. ofa-mercapto-a,a-diethylacetic acid in 50 cc. of ethanol are added slowlyin a nitrogen atmosphere to a cooled andstirred solution of 9.2 g. ofsodium in 400 cc. of ethanol. 44 g. of 6-ethoxyhexylbromide in 100 cc.of ethanol is then added gradually. The mixture is stirred for 16 hoursat room temperature. A white solid precipitates during the reaction.Without filtration, the ethanol is removed in vacuo and the residuedissolved in water. The solution is acidified, extracted with ether, andthe extract dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo, yielding 39.5 g. of a-(fi-ethoxyhexylmercapto)-a,a-diethylacetic acid, boiling at 174-179/0.4mm.

39.5 g. of a-(6-ethoxyhexylmercapto)-u,a-diethylacetic acid is refluxedwith 80 cc. of thionyl chloride for 2 hours. After removal of the excessthionyl chloride, the residue is fractionated in vacuo, yielding 37 g.of a-(6-ethoxyhexylmercapto)-u,a-diethylacetylchloride boiling at152155/ 0.5 mm.

37 g. of u-(6-ethoxyhexylmercapto)-u,a-diethylacetylchloride in 100 cc.of ether is added gradually to a solution of 15 g. of ammonia in 500 cc.of ether. After standing for hours at room temperature, water is addedto dissolve the precipitated ammonium chloride. The organic layer isseparated and dried over sodium sulfate. After removal of the ether, theresidue is fractionated in vacuo.a-6-ethoxyhexylmercapto)-oc,oc-diethylacetamide is obtained as acolorless liquid boiling at 183-185 0.3 mm. Yield 29 g.

EXAMPLE l0 oc- [Z-(Z-ethoxyelhoxy ethylmercapto] -a,u-dietlzylacetamz'de30 g. of a-rnercapto-a,a-diethylacetic acid, dissolved in 50 cc. ofethanol is added slowly in a nitrogen atmosphere to a cooled and stirredsolution of 9.2 g. of sodium in 400 cc. of ethanol. 44 g. of2-(2-ethoxyethoxy)ethylbromide in cc. of ethanol is then addedgradually. The mixture is refluxed for 16 hours at room temperature. Awhite solid precipitates during the reaction. Without filtration, theethanol is removed in vacuo, and the residue dissolved in water. Thesolution is acidified, extracted with ether, and the extract dried oversodium sulfate. After removal of the ether, the residue is fractionatedin vacuo, yielding 36 g. ofa-[2-(2-ethoxyethoxy)ethylmercapto]-a,a-diethylacetic acid boiling at184190/ 0.3 mm.

36 g. of a-[2-(2-ethoxyethoxy)ethylmercapto]-a,a-di ethylacetic acid isrefluxed with 40 cc. of thionyl chloride for 2 /2 hours. After removalof the excess thionyl chloride, the residue is fractionated in vacuo,yielding 34 g. of a[23-(2-ethoxyethoxy)ethylmercapto]-a,a-diethylacetylchloride, boiling atl27l30/0.5 mm.

34 g. of a-[2-(Z-ethoxyethoxy)ethylmercapto]-oz,oc-diethylacetylchloridein 100 cc. of ether is added gradually to a solution of 15 g. of ammoniain 500 cc. of ether. After standing at room temperature for 5 hours,water is added to dissolve the precipitated ammonium chloride. Theorganic layer is separated and dried over sodium sulfate. After removalof the ether, the residue is fractionated in vacuo.a-[2-(2-ethoxyethoxy)ethylmercapto]- x,adiethylacetamide is obtained asa colorless oil, boiling at 188-192/0.6 mm. Yield 24 g.

We claim:

1. A compound of the formula C5I5\S-(CHZ)|1OR wherein R is selected fromthe group consisting of hydrogen, lower alkyl, and lower alkoxy loweralkyl, and n is a whole number in the range 2 through 6.

2. a-(3-ethoxypropylmercapto)-u,a-diethylacetamide. 3. 04-3-methoxypropylmercapto -a,a-diethylacetamide. 4.a-(Z-ethoxyethylmercapto)-a,oz-diethylacetamide. 5. a-(Z-butoxyethylrnercapto -a,a-diethylacetamide. 6. A compound of theformula wherein R is selected from the group consisting of hydrogen,lower alkyl, and lower alkoxy lower alkyl, and n is a whole number inthe range 2 to 6.

References Cited by the Examiner UNITED STATES PATENTS 2,184,495 12/39Graenacher et al. 260-561 2,397,960 4/46 Gribbins et al. 260537 XR2,874,190 2/59 Goldberg et al. 260-561 IRVING MARCUS, Primary Examiner.

JOHN D. RANDOLPH, Examiner.

1. A COMPOUND OF THE FORMULA
 6. A COMPOUND OF THE FORMULA